Intensified ocean exploration has revealed that high pressure causes severe tremors and EEG disturbances in divers working at great depths (the High Pressure Nervous Syndrome, HPNS). There is experimental evidence that general anesthetics may antagonize the effects of pressure and thus ameliorate some of the disabling symptoms of HPNS. Similarly, high pressure antagonizes general anesthesia by anesthetic agents of many diverse types. The proposed study, a renewal of project NS13108, is designed to investigate the ways in which hyperbaric pressures alter the function of nerve cells, and to establish the membrane site(s) at which pressure and general anesthetics interact. Observed increases in nerve cell excitability and hyperbaric pressures will be explored in order to determine the pressure-response relationship for this phenomenon, and the effect of general anesthetics on it. Studies will be extended to the voltage-clamped single axon in order to examine the effects of pressure on ionic channel gating processes. Electron paramagnetic resonance spectroscopy of spin-labeled nerve membranes will be carried out to bridge the gap between previous model membrane studies and observations of functional changes in intact nerve cells at high pressures. The characterization of pressure effects and of pressure-anesthetic interactions is expected to clarify the extent to which the use of anesthetics may be expected to antagonize the effects of pressure in deep dives. In addition, the identification of the cellular sites of pressure-anesthetic antagonism may shed additional light on the cellular basis for anesthesia.